Despite the frequency at which chromosomal abnormalities occur in humans, the molecular mechanisms underlying their occurrence are poorly understood. Robertsonian translocations (ROB), whole arm exchanges between the acrocentric chromosomes 13, 14, 15, 21, and 22, are the most common, recurrent, chromosomal rearrangements in humans. ROBs have exceptionally high rates of de novo formation. We have postulated that ROBs form through two distinct mechanisms; a directive process resulting in the common rob(13q14q) and rob(14q21q), and a more random process resulting in the remaining eight rarer classes. To elucidate the mechanisms involved in ROB formation, we propose to identify the region containing the breakpoints in the two most common classes, rob(13q14q) and rob(14q21q), and clone the sequence(s) involved in the translocation formation. The hypothesis to be tested is that specific sequences are shared between the nonhomologous chromosomes 13, 14, and 21 that are properly oriented as to facilitate pairing and recombination leading to translocation formation. This hypothesis is supported by the observations of disproportionately large numbers of rob(13q14q) and rob(14q21q) with consistent breakpoints as compared to the rarely occurring, remaining classes of ROB with highly variable breakpoints. The specific aims of this proposal are to 1) further characterize and narrow the breakpoint regions on chromosomes 13, 14, and 21 and 2) test existing satellite III subfamilies from our laboratory to elucidate potential involvement in ROB formation. If the above satellite III sequences do not appear to be involved in the translocation exchanges we will then 3) identify novel sequences on the short arms of chromosomes 13, 14, and 21 around the ROB breakpoints; and 4) test these sequences to elucidate their potential role in ROB formation. The study of this common class of structural rearrangements has broader implications to understanding constitutional and acquired translocation formation, basic mechanisms for chromatin exchange, recombination differences between the sexes and nondisjunction in humans.